Genes Associated with Gynecological Tumors
BRCA1/BRCA2 Genes
BRCA1 and BRCA2 are tumor suppressor genes that play critical roles in homologous recombination repair (HRR) of DNA damage, cell cycle regulation, gene transcription, and apoptosis. Mutations or deletions in BRCA genes compromise their tumor-suppressive functions, leading to uncontrolled proliferation of cancer cells. Approximately 20%–30% of ovarian cancer cases are linked to hereditary genetic mutations, with 65%–85% of hereditary ovarian cancers caused by germline mutations in BRCA genes. BRCA1/BRCA2 testing is therefore highly significant for the prevention and management of hereditary ovarian cancer.
Women with germline mutations in BRCA1 or BRCA2 face a lifetime ovarian cancer risk of 40%–60% and 11%–27%, respectively. Multiple guidelines recommend that BRCA1 mutation carriers undergo risk-reducing salpingo-oophorectomy (RRSO) between the ages of 35 and 40 following childbearing, while BRCA2 mutation carriers may consider RRSO between 40 and 45 years. Additionally, poly ADP ribose polymerase (PARP) inhibitors provide significant therapeutic benefits for patients with BRCA mutations or homologous recombination deficiency (HRD). Mechanistically, PARP repairs single-strand DNA breaks through base excision repair. When PARP is inhibited, single-strand repair fails, activating the HRR pathway. BRCA is a key protein in the HRR pathway; with BRCA mutations, HRR cannot occur, forcing cells to rely on the error-prone non-homologous end joining (NHEJ) pathway, leading to accumulated genetic damage and selective cell apoptosis, known as the "synthetic lethality effect." PARP inhibitors are currently approved for first-line maintenance therapy following initial treatment of ovarian cancer and for the maintenance treatment of platinum-sensitive recurrent ovarian cancer.
MMR Genes
Mismatch repair (MMR) genes function to eliminate DNA replication errors (RER) and microsatellite instability (MSI). Microsatellite instability can result in the activation of proto-oncogenes or inactivation of tumor suppressor genes, leading to tumorigenesis. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant hereditary disorder caused by mutations in MMR genes. Individuals with Lynch syndrome have a lifetime risk of 40%–80% for colorectal cancer, 40%–60% for endometrial cancer, and 9%–12% for ovarian cancer. Endometrial cancer is the most common extracolonic tumor in Lynch syndrome, and such cases account for approximately 3% of all endometrial cancers, referred to as Lynch syndrome-associated endometrial cancer. Current guidelines recommend evaluating MMR or MSI in all endometrial cancer patients.
TP53 Gene
The TP53 gene is the most extensively studied tumor suppressor gene in humans. It encodes the p53 protein, a transcription factor involved in DNA repair, cell cycle regulation, and apoptosis. The p53 protein binds to DNA polymerase, inactivating the replication initiation complex. Additionally, a specific amino acid sequence in p53 exhibits transcriptional activity, activating other tumor suppressor genes to inhibit tumor growth.
Abnormalities in the TP53 gene include point mutations, loss of allele fragments, rearrangements, or deletions, which impair its DNA-binding function. In the absence of functional p53, cells fail to cease excessive replication following DNA damage, resulting in malignant tumor proliferation. TP53 mutations are highly prevalent in malignant ovarian tumors, especially high-grade serous carcinomas, while mutations are rare in low-grade serous carcinomas. TP53 mutation status is a critical marker in the pathological diagnosis of ovarian tumors.
In addition, interaction between the HPV gene product E6 and p53 protein leads to rapid inactivation of p53, a key event in the progression of cervical cancer and a molecular biomarker for predicting cervical lesion prognosis. Approximately 20%–30% of endometrial cancer cases exhibit TP53 mutations, which are closely related to risk stratification and prognosis. TP53 mutation status is also a crucial factor in molecular classification of endometrial cancer.
PD-1/PD-L1
The gene encoding programmed death protein-1 (PD-1) was first identified in 1992. PD-1 belongs to the immunoglobulin superfamily B7-CD28, a key member of the co-stimulatory molecule family. It is primarily expressed on activated T cells, B cells, natural killer cells, monocytes, and mesenchymal stem cells, playing a critical role in regulating autoimmune responses and tumor immunity.
The PD-1/PD-L1 (programmed death-ligand 1) complex suppresses lymphocyte proliferation and cytokine production in response to antigen stimulation, leading to lymphocyte exhaustion and immune tolerance. Anti-PD-1 and anti-PD-L1 antibodies can reverse immunosuppression, activating immune cells to exert anti-tumor effects. PD-1/PD-L1 is overexpressed in a variety of gynecological malignancies. For instance, in cervical cancer, PD-L1 expression rates range between 30% and 90%. Studies suggest that PD-1 antibody treatments show improved efficacy in patients with high PD-L1 expression.
Currently, monoclonal antibodies targeting PD-1 and PD-L1 have been widely applied for the treatment of advanced or recurrent cervical cancer. PD-L1 is also highly expressed in trophoblastic tumors, and studies have demonstrated significant efficacy of PD-1 monoclonal antibody therapy for resistant trophoblastic tumors.
HER2 Gene
The human epidermal growth factor receptor 2 (HER2), also known as HER2/neu, ERBB2, or CD340, is a member of the epidermal growth factor receptor family with tyrosine kinase activity. Receptor dimerization leads to tyrosine residue phosphorylation and activation of several signaling pathways that drive cell proliferation and tumorigenesis. HER2 overexpression has been observed in diseases such as breast cancer, ovarian cancer, and endometrial cancer. In epithelial ovarian cancer, patients with HER2 overexpression have worse overall survival compared to those with low or absent HER2 expression. HER2 expression is also associated with platinum-based chemotherapy sensitivity in ovarian cancer. Clinical studies have demonstrated that the HER2-targeted monoclonal antibody trastuzumab significantly extends survival in patients with advanced, recurrent HER2-positive serous endometrial carcinoma.
VEGF
Vascular endothelial growth factor (VEGF) is a heparin-binding growth factor specific to endothelial cells and promotes angiogenesis in vivo. Tumor growth, invasion, and metastasis depend on new blood vessels for nutrient and oxygen supply. Inhibition of the VEGF pathway can suppress initial tumor cell growth and metastasis. VEGF also increases vascular permeability, facilitating tumor cell entry into newly formed blood vessels and promoting metastasis. Bevacizumab, a recombinant humanized monoclonal IgG1 antibody, specifically binds to VEGF, blocking its activation of VEGF receptors (VEGFR), thereby preventing angiogenesis and reducing the tumor's nutrient supply. This helps inhibit tumor growth and metastasis. Currently, multiple guidelines recommend combining bevacizumab with chemotherapy for initial and recurrent treatment of ovarian cancer.
MYC and RAS Genes
The MYC (c-MYC, l-MYC, and n-MYC) and RAS (NRAS, KRAS, and HRAS) proto-oncogenes are closely associated with tumorigenesis. MYC overexpression is found in 20%–30% of ovarian tumors, particularly in serous tumors. In cervical cancer, MYC overexpression occurs in about 30% of cases, with levels exceeding normal by 2 to 40 times. Its expression is associated with squamous cell carcinoma differentiation and lymph node metastasis in cervical cancer. Upregulation of c-MYC not only predicts the efficacy of chemotherapy in cervical squamous cell carcinoma but also serves as a prognostic marker, with abnormal c-MYC amplification indicating a poor prognosis.
The frequency of RAS mutations in cervical cancer ranges from 40% to 100%. Of patients with RAS abnormalities, 70% also exhibit MYC amplification or overexpression, suggesting that these two genes collectively influence the prognosis of cervical cancer. In endometrial cancer, mutation rates of the KRAS gene range between 19% and 46%, with mutations typically occurring in type I endometrial cancers. Higher histological grade and more advanced clinical staging correlate with increased rates of KRAS positivity in endometrial cancer.
RB and PTEN Genes
The retinoblastoma (RB) gene and PTEN gene are both human tumor suppressor genes. RB mutations or RB protein inactivation via cyclin-dependent kinase-mediated phosphorylation disrupt the regulation of cell cycle-related gene transcription, promoting cell proliferation and cancer progression. In HPV-infected cervical cells, the E7 oncogenic protein binds to and inactivates RB protein, leading to p16 overexpression. This process is a key event in HPV-induced cervical tumorigenesis.
PTEN mutations or deletions result in the loss of phosphatase activity, removing its negative regulatory effect on cell growth. This promotes uncontrolled proliferation, malignant transformation, and tumor formation. PTEN mutations are detectable in 20% of cases of endometrial hyperplasia and 84% of endometrial cancers. PTEN mutation has also been identified as an early molecular event in type I endometrial cancer.
Other Genes
The POLE gene encodes DNA polymerase epsilon and serves as a marker for molecular classification of endometrial cancer. Patients with POLE-ultramutated endometrial cancer generally have better prognoses, with POLE mutations considered key prognostic molecular markers for treatment decisions in endometrial cancer.
Gene fusions involving NTRK and RET are rare events in gynecological tumors, but their detection is regarded as a potential indicator for pan-cancer targeted therapy. Additionally, folate receptor alpha (FRα) is overexpressed in 80% of epithelial ovarian cancers and is considered a marker of poor prognosis in ovarian cancer.
Genetic Testing for Gynecological Tumors
Cervical Cancer
The purpose of genetic testing in cervical cancer is to determine the pathological subtype and HPV association, as well as to guide targeted therapy and immunotherapy for metastatic/recurrent cervical cancer. Testing is primarily applied in the following scenarios:
- At initial diagnosis, HPV status or P16 testing is performed.
- For advanced metastatic/recurrent cervical cancer, tests for PD-L1, TMB, and MSI/MMR are recommended.
- For cervical sarcoma, testing for NTRK gene fusions is suggested.
- For locally advanced or metastatic cervical cancer, RET gene fusion testing may be considered.
Endometrial Cancer
In 2013, The Cancer Genome Atlas (TCGA) classified endometrial cancer into four molecular subtypes based on multi-omics genetic characteristics. These subtypes have since been simplified into the following:
- POLE ultramutated subtype,
- Mismatch repair-deficient (dMMR) subtype,
- No specific molecular profile (NSMP) subtype,
- p53 abnormal subtype.
Compared to conventional clinicopathologic classification, molecular subtyping of endometrial cancer does not rely on tumor morphology and has the potential to more accurately guide prognostic risk assessment and treatment decisions.
The POLE ultramutated subtype typically involves high-grade tumors with deep myometrial and lymphovascular space invasion, yet it has the best prognosis among the four subtypes. Its favorable prognosis, regardless of adjuvant therapy, suggests the possibility of de-escalating treatment in this subtype. The dMMR subtype, found in advanced metastatic/recurrent cases, is sensitive to immune checkpoint inhibitors and shows intermediate overall prognosis. The NSMP subtype, which accounts for about 50% of endometrial cancer cases, also has an intermediate prognosis. The p53 abnormal subtype is the most aggressive, with the poorest prognosis, though it demonstrates significant benefits from adjuvant treatments such as chemotherapy, suggesting the potential need for escalated treatment in this subtype.
Genetic testing for endometrial cancer is primarily used in:
- Comprehensive genomic evaluation and molecular subtyping may be considered for all newly diagnosed patients, including testing for POLE mutations, MSI/MMR, p53 abnormalities, and HER2 expression.
- NTRK gene fusion testing may be considered for patients with metastatic or recurrent endometrial cancer.
- TMB testing can also be considered.
- Universal screening for mismatch repair protein deficiency should be undertaken in all endometrial cancer patients, and germline testing is recommended for those found to be positive.
Ovarian Cancer
Genetic testing in ovarian cancer is a reliable method for identifying hereditary predispositions and is a key factor in selecting targeted therapies. With the increasing role of targeted drugs, such as PARP inhibitors, in the treatment of ovarian cancer, genetic testing is becoming an integral part of comprehensive ovarian cancer management. Testing is advised for all patients at any stage if it has not been previously performed.
The main components of ovarian cancer genetic testing include:
- At initial diagnosis, BRCA1/BRCA2 mutations and homologous recombination deficiency (HRD) should be tested.
- At recurrence, any genetic tests with potential therapeutic implications, which were not previously performed, should be completed. These include but are not limited to BRCA1/BRCA2, homologous recombination repair status, mismatch repair, microsatellite instability, TMB, HER2, FRα, RET, BRAF, and NTRK. For rare pathological subtypes, broader and more comprehensive testing is particularly critical.